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  • 1
    Keywords: brain ; RECEPTOR ; MODEL ; GENE ; transcription ; DRUG ; MICE ; TRANSCRIPTION FACTOR ; TARGET ; NERVOUS-SYSTEM ; c-Fos ; STRESS ; transgenic ; AMPHETAMINE ; cocaine ; CORTICOSTERONE ; DOPAMINERGIC TRANSMISSION ; glucocorticoid receptor ; INDIVIDUAL VULNERABILITY ; INDUCED SENSITIZATION ; intravenous ; mifepristone ; PROGRESSIVE RATIO SCHEDULE ; SEEKING BEHAVIOR ; self-administration ; sensitization
    Abstract: Several findings suggest that glucocorticoid hormones are involved in determining the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor. In this study, we show that the selective inactivation of the GR gene in the brains of mice profoundly flattened the dose - response function for cocaine intravenous self-administration and suppressed sensitization, two experimental procedures considered relevant models of addiction. Furthermore, administration of a GR antagonist dose- dependently reduced the motivation to self-administer cocaine. Importantly, the absence of GR did not modify the basal behavioral and molecular effects of cocaine but selectively modified the excessive response to the drug spontaneously present in certain vulnerable individuals or induced by repeated drug exposure in others. In conclusion, we provide the first genetic evidence that the GR gene can modulate cocaine abuse. This suggests that targeting GR function in the brain could provide new therapeutic strategies to treat cocaine addiction for which there is no available treatment
    Type of Publication: Journal article published
    PubMed ID: 12805318
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  • 2
    ISSN: 1432-1106
    Keywords: Acetylcholine release ; Cholinergic neurons ; Dopamine release ; Dopaminergic transplants ; In vitro release ; Neuronal transplantation ; Nigrostriatal system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of the study was to examine the influence of intrastriatal dopaminergic grafts on the functioning of striatal cholinergic neurons using an in vitro superfusion method. Rats bearing unilateral 6-hydroxydopamine lesion of the nigrostriatal dopaminergic system received a cell suspension obtained from ED 14 rat embryonic mesencephali which was injected into the denervated striatum. Lesioned animals displayed an ipsilateral rotation in response to amphetamine (5 mg/kg i.p.). This rotational response disappeared following grafting and there was even a significant contralateral rotation in response to the drug. Apomorphine (0.1 mg/kg s.c.) induced a contralateral rotation following the lesion. This latter response was attenuated in the grafted group. Three months after grafting 350 μm thick slices were prepared from striata from the control and experimental sides of lesioned and graft-bearing animals. The slices were preincubated either with 3H-dopamine (10-7 M) or 3H-choline (10-7 M) and then superfused with an oxygenated Krebs-Ringer solution. Stimulation with electrical pulses following preincubation with 3H-dopamine elicited a marked increase of tritium outflow from control slices. Stimulation-evoked overflow was of similar magnitude from slices from striata containing the graft, while it was much reduced in slices from lesioned striata. Amphetamine markedly potentiated the effect of electrical stimulation in slices obtained from control and graft-containing striata. Nomifensine (a dopamine uptake blocker) led to a significant decrease of the overflow of 3H-acetylcholine evoked by electrical stimulation from control striatal slices. This inhibition was antagonized by domperidone, a D2 dopamine receptor blocker, a finding which indicates that the action of nomifensine was indeed due to a potentiation of the action of endogenous dopamine released by the electrical stimulation. A similar, although somewhat attenuated, action of nomifensine and domperidone was observed for striatal slices containing the graft. Amphetamine inhibited the stimulation evoked overflow of 3H-acetylcholine in a dose-dependent manner from striatal slices obtained both from the intact and experimental sides of graft-bearing animals, while it had no action on slices from denervated striata. Finally, the dose-response curve for the inhibition of 3H-acetylcholine release by apomorphine was significantly shifted to the left for slices from the lesioned striata as compared with control slices. This leftward shift was totally abolished in the slices from the graft-containing striatum. These results indicate that the dopaminergic inhibition of the striatal cholinergic interneurons, abolished by the lesion, is restored by intrastriatal dopaminergic grafts both in vitro and in vivo. On the other hand the lack of correlation between the in vivo and the in vitro effects (rotational response vs. inhibition of 3H-acetylcholine release) suggest that the effect of such grafts on rotational behavior cannot be explained solely by their action on the striatal cholinergic neurons.
    Type of Medium: Electronic Resource
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